Submissions for variant NM_000256.3(MYBPC3):c.3234G>A (p.Trp1078Ter)

dbSNP: rs866966651

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002274740	SCV002559677	likely pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	Reported in association with hypertrophic cardiomyopathy (Millat et al., 2010; Calore et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25740977, 20800588)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509824	SCV002819844	likely pathogenic	Cardiomyopathy	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3234G>A (p.Trp1078X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 210186 control chromosomes. c.3234G>A has been reported in the literature in individuals affected with Cardiomyopathy (Restrepo-Cordoba_2017, Calore_2015, Biagini_2014, Mademont-Soler_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided a clinical-significance assessment for this variant in ClinVar after 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101559	SCV003439696	pathogenic	Hypertrophic cardiomyopathy	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1078*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 25740977). ClinVar contains an entry for this variant (Variation ID: 1700491). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004651968	SCV005144231	pathogenic	Cardiovascular phenotype	2024-04-15	criteria provided, single submitter	clinical testing	The p.W1078* pathogenic mutation (also known as c.3234G>A), located in coding exon 30 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3234. This changes the amino acid from a tryptophan to a stop codon within coding exon 30. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Millat G et al. Clin Chim Acta, 2010 Dec;411:1983-91; Helms AS et al. Circ Cardiovasc Genet, 2014 Aug;7:434-43; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Calore C et al. J Med Genet, 2015 May;52:338-47; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.